title: Identification of Hck inhibitors as hits for the development of antileukemia and anti-HIV agents.
abstract: Hematopoietic cell kinase (Hck) is a member of the Src family of non-receptor protein tyrosine kinases. High levels of Hck are associated with drug resistance in chronic myeloid leukemia. Furthermore, Hck activity has been connected with HIV-1. Herein, structure-based drug design efforts were aimed at identifying novel Hck inhibitors. First, an in-house library of pyrazolo[3,4-d]pyrimidine derivatives, which were previously shown to be dual Abl and c-Src inhibitors, was analyzed by docking studies within the ATP binding site of Hck to select the best candidates to be tested in a cell-free assay. Next, the same computational protocol was applied to screen a database of commercially available compounds. As a result, most of the selected compounds were found active against Hck, with Ki values ranging from 0.14 to 18.4 μM, confirming the suitability of the computational approach adopted. Furthermore, selected compounds showed an interesting antiproliferative activity profile against the human leukemia cell line KU-812, and one compound was found to block HIV-1 replication at sub-toxic concentrations.
authors.affiliation: Dipartimento Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. De Gasperi 2, 53100 Siena, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Tintori
authors.forename: Ilaria
authors.initials: I
authors.lastname: Laurenzana
authors.forename: Francesco
authors.initials: F
authors.lastname: La Rocca
authors.forename: Federico
authors.initials: F
authors.lastname: Falchi
authors.forename: Fabio
authors.initials: F
authors.lastname: Carraro
authors.forename: Alba
authors.initials: A
authors.lastname: Ruiz
authors.forename: José A
authors.initials: JA
authors.lastname: Esté
authors.forename: Miroslava
authors.initials: M
authors.lastname: Kissova
authors.forename: Emmanuele
authors.initials: E
authors.lastname: Crespan
authors.forename: Giovanni
authors.initials: G
authors.lastname: Maga
authors.forename: Mariangela
authors.initials: M
authors.lastname: Biava
authors.forename: Chiara
authors.initials: C
authors.lastname: Brullo
authors.forename: Silvia
authors.initials: S
authors.lastname: Schenone
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D001665:Binding Sites; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D015658:HIV Infections / Q000188:drug therapy; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007700:Kinetics; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D017434:Protein Structure, Tertiary; D051572:Proto-Oncogene Proteins c-hck / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity; D011743:Pyrimidines / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C014175:pyrazolo(3,4-d)pyrimidine; D051572:Proto-Oncogene Proteins c-hck
keywords: HIV-1; Hck; docking; kinases; leukemia